The burden of chronic viral infections worldwide is extraordinarily high, with HIV-1 and HCV foremost causes of morbidity and mortality. Through a variety of immune evasion mechanisms these pathogens establish long-term chronic viremia in their infected hosts, leading to immune destruction in the case of HIV-1 and liver disease and hepatocellular carcinoma in the case of HCV. On the other hand, it is not clear why a significant portion of persons infected with these viruses are able to spontaneously control these infections and avoid their complications. The mechanisms underlying control of HCV and HIV-1 remain incompletely understood but have enormous implications for development of successful therapeutic approaches. There is already strong evidence for a genetic basis of spontaneous control of each of these viruses. Recent candidate gene studies have found that HLA-B*57 associated with both spontaneous clearance of HCV and elite control of HIV-1. Unbiased genome wide association surveys (GWAS) represent the best opportunity to identify the multiplicity of polymorphisms that contribute to the clinical phenotype of clearance. A recent GWAS found an extraordinarily strong relationship between a SNP in the IL28B gene and the likelihood of interferon therapy- induced clearance. Confirmatory testing revealed that the favorable IL28B genotype is also associated with spontaneous HCV clearance. However, it is evident that only with larger GWAS surveys and other novel fine mapping scans of immune loci such as HLA will we identify other genes less obviously contributing to spontaneous HCV clearance. Even more importantly, translating genotype into phenotype using functional assays for HCV clearance will be essential to put these findings in biological context. The existence of HCV and HIV-1 controller datasets allows us a unique opportunity to identify genetic associations favorable to control of both viruses that might not otherwise be appreciated by analysis of a single dataset. The overall goal of this proposal is to assess novel host genetic associations with HCV control and to elucidate their underlying mechanisms. In Aim 1a, we will, collaborating on the largest GWAS of HCV spontaneous clearance to date with Dr. David Thomas, comprehensively assess the most likely candidate genes that control HCV. In parallel and in concert with our collaborators at the Broad Institute, we will perform a novel ImmunoChip scan (Aim 1b) that extensively fine maps a smaller number of key immune and inflammatory loci postulated to be involved in not only autoimmune diseases, but also in viral clearance, including HLA loci. Because of the PIs'collective expertise in innate and adaptive immunity, we are well-poised to functionally evaluate our early findings (IL28B, B*57) into functional studies involving hepatocyte-based models, and PBMCs (Aim 2a,b). We will also build a prospective cohort to continually validate new candidates (Aim 2c). Finally, we will exploit the existence of two unique controller datasets (HCV and HIV-1) using cross-disease analysis to determine whether there are unappreciated loci common to both infections that may not be revealed with analysis of either alone (Aim 3a). We will be particularly interested in identifying and confirming polymorphisms common to control of both infections (Aim 3b). Using the combination of powerful new technologies and large, prospectively collected cohorts, we are now in the exciting position of rationally and comprehensively identifying and functionally evaluating key host determinants of HCV clearance. PUBLIC HEALTH RELEVANCE: HCV and HIV pose an enormous health care burden as chronic infections, yet there is a small portion of patients who are capable of successful clearance or control of these infections. Host genes likely underlie these variable outcomes, and initial promising results point to a number of possible markers. Using powerful genomic tools, we will comprehensively identify additional genes and decipher the means by which they produce improved clearance of these debilitating infections.